JP2012500035A - Passive fluid flow regulator - Google Patents

Abstract

  A passive fluid flow regulator (1) having a fluid inlet suitable for being connected to a fluid reservoir and a fluid outlet (13) suitable for being connected to a patient's body is disclosed. The regulator comprises a rigid substrate (2) and an elastic membrane (3), which are rigidly connected together to define a chamber (6) between the rigid substrate and the elastic membrane, (6) is separated from the fluid outlet while the membrane (3) has a first surface (12) on the opposite side of the chamber (6) connected to the fluid inlet. The membrane (6) has a plurality of through holes (15) adjacent to the chamber to define a path for fluid from the fluid inlet to the fluid outlet, so that the fluid has sufficient pressure. It is flexible so that it can contact the substrate when applied to the first surface. The plurality of through holes reduce the fluid resistance of the regulator so that when the fluid pressure increases, the fluid flow rate is substantially constant as a function of the pressure applied to the first surface within a predetermined pressure range. It is configured to close in sequence to increase.

Description

  The present invention relates to a passive fluid flow regulator, and more particularly to a passive fluid flow regulator of the type used in the field of drug delivery, for example, a drug for pain management is a liquid or It is related with the said regulator which is gas. The flow regulator of the present invention can also be used to drain cerebrospinal fluid (CSF) for hydrocephalus patients. The invention further relates to a method of manufacturing such a fluid flow regulator and an apparatus comprising the fluid flow regulator.

  In contrast to active drug infusion devices, passive drug infusion devices use a drug reservoir where pressure is applied rather than a pump to deliver the drug. The known problem with such passive devices is that the flow rate of the drug to the supply location, which may be the patient's body, for example, depends on this amount, as long as the pressure in the reservoir depends on the amount of drug remaining in the reservoir. There is a risk of change. Accordingly, such passive devices are typically provided with a fluid flow regulator that ensures that the drug flow rate is as constant as possible relative to the amount of drug remaining in the reservoir.

  An example of such a passive drug flow regulator is available by the Applicant under the registered name “Chronoflow” and is disclosed in US Pat. The device comprises a fluid inlet suitable for connection to a fluid reservoir and a fluid outlet suitable for connection to a patient's body. The device comprises a rigid substrate and an elastic membrane, which are rigidly connected together at a peripheral connection portion so as to define a chamber between the rigid substrate and the elastic membrane. The chamber is connected to the fluid outlet, while the membrane has a first surface on the opposite side of the chamber connected to the fluid inlet. The membrane has a central through hole adjacent to the chamber to define a path for fluid from the fluid inlet to the fluid outlet so that the fluid exerts a pressure on the first surface that is greater than a first predetermined threshold. It is flexible so that it can contact the substrate when applied. When the membrane comes into contact with the substrate in the region of the central through-hole of the membrane, this closes the through-hole and prevents fluid from flowing through the through-hole.

  The apparatus further comprises a flow regulator open passage etched into the substrate having an inlet facing the central through-hole of the membrane and an outlet connected to the outlet of the apparatus. This passage is in the shape of a helical curve, so that the more pressure is applied to the membrane, the more it closes the passage, thereby allowing fluid to flow in the chamber to find a way out of the chamber. Let it flow. As a result, as the pressure applied to the membrane increases, the length of the fluid path placed inside the flow regulator passage increases and the fluid resistance of the device also increases. Therefore, the flow rate can be kept approximately constant within a predetermined range of the storage tank pressure.

  However, the manufacture of such a device is complicated and expensive. In practice, the substrate must be etched with a special pattern that is fairly delicate with respect to the degree of accuracy, and this degree of accuracy must be respected for a properly functioning flow conditioner. Thus, not only does the manufacture of the substrate require special additional steps, but these steps are also delicate to implement. Depending on the dimensions of the device, special materials such as SOI should be used in the manufacture of the substrate, and the substrate becomes more and more expensive.

  In addition, the device produced by this method is then configured for one specific combination of parameters relating to drug delivery, ie a predetermined reservoir pressure range and average flow rate.

  Hydrocephalus is usually due to blockage of CSF efflux in the subarachnoid space in the ventricle or above the brain. Hydrocephalus treatment is surgical and placement of a ventricular catheter (eg, a tube made from silastic ™) into the ventricle to bypass the flow obstruction / dysfunctional arachnoid granule And draining excess fluid from where it can be reabsorbed into other body cavities.

  Many CSF shunts have been based on the principle of maintaining a constant intracranial pressure (ICP) regardless of the CSF flow rate. The CSF shunt is configured to interrupt the flow of CSF when different pressures between the inlet and outlet of the CSF shunt are reduced to a predetermined extent called the shunt opening pressure.

  An example of an ICP shunt is shown in US Pat. No. 6,057,031 to Hakim, which allows fluid drainage between different parts of a patient's body, particularly to drain cerebrospinal fluid from the ventricle into the bloodstream. Surgical drain valve device used to control (so-called ventricular-atriotomy).

  Clinical experience has proven that this principle of shunt surgery is not an ideal solution. For example, rapid increases in ICP due to posture changes, exercise, or pathological pressure waves cause excessive CSF drainage. Several reports in the literature (Asschoff et al., 1995) point out the challenges resulting from this over-excretion, and in particular, the significant narrowing of the ventricles is the main factor leading to malfunction of the implanted shunt surgical device Has been pointed out. The reason is that the ventricular wall may collapse around the ventricular CSF shunt device, and particles (cells, debris) may enter the shunt device.

  U.S. Pat. No. 6,053,836 to Drake et al. Is a fairly complex anti-siphoning device that controls one of the main chambers by controlling the pressure in a gas-filled chamber and regulating the flow. An example of a shunt that aims to overcome the above difficulties by proposing a device that allows percutaneous selection of flow resistance by being in pressure communication with a sexual wall is described.

  The use of a programmable valve has been associated with a reduced risk of proximal occlusion and overall shunt reconstruction. One possible explanation for the difference between the two populations studied is that the programmable valve allowed the physician to notice clinical signs and symptoms and / or radiological evidence of over-excretion. Later, it may be possible to prevent such ventricular collapse by increasing the valve pressure setting. In this way, proximal occlusion is prevented and shunt reconstruction surgery is avoided. One such adjustable valve is described in US Pat. However, due to the elastic properties of the diaphragm material, maintenance of the embedded valve may be required. Further, adjusting the flow rate of this adjustable valve after implantation may require surgery.

  Another adjustable valve mechanism described in Watanabe in US Pat. No. 6,053,834 includes two parallel fluid flow channels, each channel including a flow regulator and an on / off valve. Fluid flow through the channel is manually controlled by touching an on-off valve through the scalp. Watanabe's device can be controlled by touching through the scalp, ie without surgical intervention, but requires patient and / or physician interest in valve settings.

  One system described in U.S. Patent No. 5,639,086 by Nissels describes a dual path anti-siphoning and flow control device, both paths functioning together in the device. During normal flow, both the first and second paths are open. When excess flow is detected, the first path closes and the flow is diverted to a high resistance second path. While the second pathway maintains the discharge rate within a physiological range, the flow rate is reduced to 90%, thereby preventing deleterious complications due to over-discharge. However, this device is intended for use with shunt systems that include a valve for controlling the flow rate and should be placed distal to the valve that causes troublesome surgery due to the additional material to be implanted. is there. The system can be used as a stand alone only for low pressure flow control valves.

US Pat. No. 6,203,523 U.S. Pat. No. 3,288,142 US Pat. No. 5,192,265 U.S. Pat. No. 4,551,128 US Pat. No. 4,781,673 US Pat. No. 6,126,628

  The primary object of the present invention is to improve the known apparatus and method. More specifically, it is an object of the present invention to propose a passive fluid flow regulator that overcomes the above disadvantages.

  Another object of the present invention is an alternative passive fluid flow regulator that is easy and inexpensive to manufacture and provides additional flexibility as far as the regulator's usage is concerned. Is to compensate for the disadvantages of the prior art mentioned above.

  In order to achieve this object, embodiments of the present invention specifically relate to a regulator as described above, wherein the regulator membrane comprises at least one further through-hole adjacent to the chamber, said further penetration Fluid flows through the further through-hole when the hole applies a pressure to the first surface of the membrane that is greater than the first predetermined threshold but less than the second predetermined threshold. It is configured to be able to. The membrane and further through-holes are further substantially linear, preferably constant, as a function of the pressure applied to the first surface of the membrane with the fluid flow rate approximately in the range from the first predetermined threshold to the second predetermined threshold. Including a regulator configured to be

  According to a preferred embodiment, the membrane may comprise n additional through holes adjacent to the chamber, each j th further through hole being greater than the j th predetermined threshold (j + 1) ) When a pressure smaller than the first predetermined threshold is applied to the first surface of the membrane, the fluid is configured to flow through the jth further through-hole. Again, the membrane and the n additional through-holes are further of a pressure applied to the first surface of the membrane within a fluid flow rate range from approximately the first predetermined threshold to the (n + 1) th predetermined threshold. It is configured to be approximately linear, preferably constant, as a function.

  The through-hole preferably has a shape such that there are no sharp edges, which shape can belong to a group comprising circular, elliptical, oblong or elongated shape.

  According to another embodiment of the present invention, a second substrate can be attached to the first surface side of the membrane to implement a bidirectional fluid flow regulator.

  The present invention further relates to an apparatus comprising the fluid flow regulator disclosed above, and provides a manufacturing method for such a regulator.

1 is a simplified cross-sectional view of a fluid flow regulator according to a preferred embodiment of the present invention, wherein the regulator receives a first pressure value. FIG. FIG. 2 is a simplified cross-sectional view of the fluid flow regulator of FIG. 1, wherein the regulator receives a larger second pressure value. FIG. 6 is a simplified plan view of a membrane according to a further exemplary embodiment of the present invention. FIG. 6 is a simplified plan view of a membrane according to a further exemplary embodiment in addition to the present invention. FIG. 3 is a simplified cross-sectional view of a fluid flow regulator according to a first alternative embodiment of the present invention. FIG. 7 is a simplified cross-sectional view of a fluid flow regulator according to a second alternative embodiment of the present invention. FIG. 6 is a simplified plan view of a membrane according to a further exemplary embodiment of the present invention. 5b is a simplified plan view of a thin film intended to cooperate with the membrane of FIG. 5a. FIG. FIG. 5b is a simplified plan view of the membrane of FIG. 5a when covered with the thin film of FIG. 5b. FIG. 6 is a simplified plan view of a membrane covered with a thin film according to a further exemplary embodiment of the present invention. 6 is a graph illustrating typical flow versus pressure characteristics for a passive self-adjusting hydrocephalus valve. 4 is a graph illustrating nominal characteristics of a regulator according to the present invention. The figure which shows 2nd Embodiment of the regulator by this invention. The figure which shows 2nd Embodiment of the regulator by this invention. Sectional drawing of 2nd Embodiment. The graph which illustrates the simulation characteristic of 2nd Embodiment. The graph which illustrates the simulation characteristic of other embodiment. The figure which shows the modification of 2nd Embodiment. The figure which shows the structure of a pressure sensor. The figure which shows the other structure of a pressure sensor. The graph which shows the prediction of the bending stress of a film | membrane. The graph which shows the FEM simulation of the development of the bending stress by pressure. The graph which shows the FEM simulation of a detector signal versus pressure. A graph illustrating the sensitivity of the sensor per mbar of pressure and per volt of bias. The figure which shows other embodiment of a pressure sensor.

  Other features and advantages of the present invention will become more apparent upon reading the following detailed description of preferred embodiments given with reference to the accompanying drawings, which are provided as non-limiting examples.

  1 and 2 show a simplified cross-sectional view of a fluid flow regulator according to a first embodiment of the present invention, where the overall behavior of the regulator with respect to the pressure applied to the regulator is as described above. Similar to the prior art device regulator.

  In practice, the fluid flow regulator 1 shown in these drawings comprises a rigid substrate 2 and an elastic membrane 3, the rigid substrate 2 and the elastic membrane 3 being predetermined to define a chamber 6 therebetween. The connecting portion 4 is firmly connected. The substrate and the film can be assembled by direct bonding or anodic bonding depending on the material of the substrate.

  Typically, the bonding portion 4 of both the substrate and the film can have a roughness in the range of 0.5-100 nm RMS to prevent any leakage. As a non-limiting example, the coupling portion is placed around both the substrate and the membrane, and the base ensures a central chamber for defining the chamber 6 when the flat membrane is joined to the substrate shoulder. Thus, the flat central portion 8 surrounded by the annular shoulder portion 9 is provided. Obviously, the shoulder may have other shapes not exceeding the scope of the present invention, for example a rectangle.

  The shoulder 10 is further provided with an integral membrane for the purpose of wrapping without playing a role in the practice of the present invention. The substrate is preferably made from silicon or Pyrex®, while the film is preferably made from silicon. The film may be bonded to the substrate by any conventional bonding method.

  Alternatively, the substrate may be made of plastic materials such as SAN and polycarbonate by hot embossing or injection molding.

  Typical preferred dimensions for the device are as follows: the membrane may be approximately 50-150 μm thick while the chamber may be approximately 10-50 μm high.

  The membrane 3 has a first surface 12 on the opposite side of the chamber side, the first surface 12 being connected to a fluid inlet (not shown) on the fluid reservoir side, while the chamber is at the fluid outlet 13. Connected and the fluid outlet 13 itself is intended to be connected to the patient's body for drug delivery in this application. Of course, as will be explained later in the description, other applications are possible with this regulator according to the invention.

  The membrane further has a number of through holes 15 adjacent to the chamber so as to define a path for the drug to be delivered through the regulator according to the invention.

  As just described, in view of the conventional conditions of use of the drug delivery device, in the pressure range of approximately 0-600 mbar, the drug delivery device is approximately 1 ml / h of a drug having properties similar to water at 20 ° C. Should be supplied at a constant flow rate.

  FIG. 1 corresponds to the situation where the pressure applied to the membrane 3 is small so that the membrane 3 is substantially flat, and the respective pressures on both sides of the membrane are roughly balanced.

  When the pressure applied to the first surface 12 is increased, the film is distorted and bent towards the substrate 2 inside the chamber 6, as shown in FIG. 1b.

  Furthermore, it can be seen from FIG. 2 that the through holes 15 are distributed throughout the membrane, so that when the membrane is bent, some through holes are blocked in response to pressure and others remain open. There may be.

  In practice, the Applicant has experimented and the conclusion is that a membrane with a given number of through holes with a given distribution is produced so that the pressure range can be divided into sub-ranges. Each sub-range corresponds to a unique number of closed through-holes 15 so that the fluid flow rate can be kept approximately constant within the entire range.

  Thus, considering a given one through-hole in the membrane, when a fluid applies a pressure on the first surface 12 that is greater than a first predetermined threshold, the pressure causes the fluid to pass through the through-hole. The adjacent through-hole passes fluid through the through-hole only if the pressure applied to the first surface is less than a second predetermined threshold, etc. And still flow. When the last through hole is plugged, the fluid can no longer flow through the device, so the regulator according to the invention serves as an overpressure protection system.

  Advantageously, the membrane and the through-hole have fluid flow rates approximately from a first predetermined threshold (corresponding to the most central hole occlusion) to an (n + 1) -th threshold corresponding to the n-th external through-hole. It is arranged to be substantially constant with respect to the pressure applied to the first surface in the range.

  The main parameters govern the choice of membrane thickness, chamber thickness or gap between the membrane and the substrate, and the number / diameter of the through-holes, the main parameters being the hole diameter tolerance and the membrane / This is the tolerance of the gap thickness.

  It should be noted that the regulator has great flexibility in defining the flow versus pressure distribution. In practice, the regulator can be configured so that the chart has a substantially flat or a slope different from zero. For example, the chart can have a negative slope without departing from the scope of the present invention.

  From a general point of view, the through holes preferably have a shape without sharp edges to avoid stress concentration. While the shape of the through hole can be different from one hole to the other, the shape can preferably belong to a group including circular, elliptical, oblong and elongated shapes. Figures 3a and 3b show examples of through hole shapes and distributions in an unrestricted manner.

  As shown in FIG. 3a, an elliptical or oblong hole may be useful in creating a more continuous conditioning system.

  In practice, the three elliptical holes 301, 302, 303 are constructed on a circular membrane 300 having a geometry of these elliptical holes that is not particularly radial. These holes are continuous in terms of fluid resistance, such as the second hole 302 begins to close below or just under the pressure required to completely close the first hole 301 located in the center of the membrane. Set to have sex.

  The holes can advantageously be arranged such that a helical curve can be drawn by joining the centers of the through holes with a line.

  The geometry of the pores must be selected according to the membrane deflection characteristics.

  It should be noted that continuous passages, for example in the form of a helix, are not recommended as long as the flexibility of the membrane is changed significantly. However, special designs, such as the exemplary design of FIG. 3b, can be used with the distribution of holes created by rotation about an axis perpendicular to the membrane. FIG. 3b shows a hole configured as part of a helical curve, the length of each zone being chosen so as not to significantly change the flexibility of the membrane.

  Clearly, the thinner the holes, the more difficult it is to etch the holes during the manufacturing process. Those skilled in the art will not encounter certain difficulties in applying the present disclosure to construct holes that meet the needs of those skilled in the art without departing from the scope of the invention.

  Figures 4a and 4b show two further embodiments of the regulator according to the invention, which are bidirectional.

  In practice, it is possible to bond the second substrate to the first surface side of the membrane, so that the membrane can deform and provide the same adjustment effect in both directions.

  In FIG. 4a, the membrane 401 has a flat center 402 and a peripheral shoulder 403, and the first substrate 410 and the second substrate 420 are on both sides of the membrane so as to define similar chambers 406 on both sides of the membrane. And joined to the peripheral shoulder 403.

  Both substrates have at least one hole 411, 421 to define an outlet / inlet depending on the direction of fluid flow, while the membrane has a plurality of through holes 415 similar to the previously described through holes. Have.

  In FIG. 4b, the membrane 501 is flat, while each of the substrates 510, 520 has holes 511, 521 located in the flat central portions 512, 522 of the substrates 510, 520, similar to both sides of the membrane. Coupled with the membrane at peripheral shoulders 513, 523 to define chamber 506.

  Here again, the membrane has a plurality of through holes 515 similar to the through holes already described above.

  It should be noted that the embodiment of FIG. 4b is preferred over the embodiment of FIG. 4a as long as it is easier to manufacture and thus cheaper. However, this should not be construed as a limitation of the invention, which is the protection scope of the invention, and equivalents are naturally possible.

  With respect to the manufacture of the regulator according to the invention, conventional steps can be carried out.

  The substrate can be made from silicon or Pyrex® while the flat center can be made by an isotropic wet etching step when a peripheral shoulder is present.

  Alternatively, as already mentioned, the substrate may be made of plastic materials such as SAN and polycarbonate by hot embossing or injection molding.

  The membrane may preferably be made from silicon in terms of the particularly suitable mechanical properties of this material. While the membrane may be further machined by wet etching, dry etching may be used for the through-holes in the membrane. An anti-bonding layer on the film and / or substrate may be required to prevent film sticking onto the substrate, typically during assembly. For silicon films and Pyrex® substrates, a typical anti-bonding layer is silicon nitride.

  Preferably, special care should be taken with respect to the preparation of different surfaces of the device, i.e. films or substrates intended to contact each other. In practice, undesired particles or dust that could impair the operation of the device should not be found on the surface of the membrane and the substrate, especially in the vicinity of the through-holes of the membrane. Furthermore, both the surface of the substrate and the surface of the membrane are in the range of 0.5-100 nm RMS to prevent any leakage between the surface of the substrate and the surface of the membrane when the membrane deforms and contacts the substrate. Can have roughness.

  According to a preferred embodiment, the outlet holes of the regulator can be placed directly on the membrane in order to simplify the substrate manufacturing method.

  Depending on the thickness required for the film, a silicon wafer perforated on the etched substrate can be easily joined. In practice, silicon wafers with a thickness of 100 μm are usually available on the market and can be used directly after the through holes have been etched.

  Other fabrication methods can be implemented instead of the method described above, which is more flexible with respect to the membrane design in the case of a non-directional regulator device.

  In practice, a membrane with several holes for each of the finally required through-holes can be constructed, while the thin additional layer covers the entire first surface of the membrane. Prior to using the membrane, further layers are then cut to open the required through holes according to the given specifications.

  In a preferred implementation of this fabrication method, the film can be covered with a sacrificial layer of aluminum or silicon oxide before patterning the holes in the film by dry etching. Each of the finally required through-holes can be configured, i.e., for example, four holes for each pressure subrange. The sacrificial layer can then be covered with a thin additional layer, such as a polymer layer, to close all these holes. Additional layers can be applied by any suitable conventional action such as spinning or lamination.

  The membrane is then bonded to the substrate, and the through-holes are empirically created by applying negative pressure in the regulator chamber before cutting off additional layers with the sacrificial layer using a laser, hot wire or spark, etc. Can be finished.

  Obviously, it is also possible to apply a positive pressure to the first surface of the membrane to finish or provide the through-holes, or the sacrificial layer, particularly the substrate and membrane, without departing from the scope of the present invention. Can be removed before assembling.

  The largest hole is preferably made to have a diameter that is slightly smaller than the nominal calculated diameter, even if the worst case is considered in terms of diameter tolerances. The adjacent hole should have a gradually smaller diameter than the first hole. The flow rate can be measured by applying a negative pressure in the chamber, and the next hole to be opened to maintain a substantially constant flow rate can also be predicted.

  Using this method, the same device can be imaged and removed to be suitable for adjusting fluid flow over a large range of flow values using only one general design.

  Furthermore, this method avoids the otherwise required etching accuracy problem, i.e. lowers the cost of the apparatus and reduces the dimensions.

  Figures 5a, 5b and 5c show a simplified plan view of a further exemplary embodiment of the device according to the invention. More precisely, FIG. 5a shows a membrane having a specific design and further having a specific design for attaching the polymer thin film illustrated in FIG. 5b, the cooperation of these two elements being shown in FIG. It can be seen from 5c.

  On the other hand, the membrane 600 has a central hole 601 and three series of through holes 602, 603, 604.

  Each of these series of through holes includes five through holes, which are here aligned on the radius of the membrane in a non-limiting and illustrative manner. The three series of through holes are, for example, regularly spaced from each other at an angle, and the present invention is not limited to this particular embodiment.

  A given series of through holes, as described above in connection with FIGS. 1 and 2, provides a predetermined flow rate of fluid within a given pressure range if this series of through holes is used as is. Is configured to be able to maintain the value of. Each series of through-holes is configured to accommodate its own fluid flow rate.

  On the other hand, the thin film 610 illustrated in FIG. 5 b having a central hole 611 and a plurality of slits 612 disposed opens a corresponding series of through holes when the thin film is placed on the membrane 600. Thus, the relative rotation between the film and the membrane does not coincide with any of the series of through holes 602, 603, 604, or any one, any two, or all three of the slits. It is configured so that it can be selectively matched. In practice, a thin film will cause the first of the membrane when pressure is applied to the membrane (using positive pressure applied from the first surface side of the membrane or negative pressure applied from the chamber side). It should have mechanical properties such that a thin film can be applied to the surface.

  FIG. 5c illustrates a configuration in which all three series of through holes are open.

  Thus, for example, if the through-holes are configured so that the series of through-holes 602, 603, 604 correspond to fluid flow rates of 1, 2, and 4 ml / h, respectively, It can be reached by the appropriate angled position of the thin film 610 above, these values are 1 ml / h (a series of through holes 602 are open), 2 ml / h (a series of through holes 603 are open) 3 ml / h (a series of through holes 602 and 603 are opened), 4 ml / h (a series of through holes 604 are opened), and 5 ml / h (a series of through holes 602 and 604 are opened) 6 ml / h (a series of through holes 603, 604 are open) and 7 ml / h (a series of through holes 602, 603, 604 are open).

  The apparatus is preferably provided with indicia 620 indicating the value of the fluid flow rate as a function of the angular position of the thin film on the membrane, and the thin film further includes precise and relative adjustment between the thin film and the membrane. Corresponding indicia 621 may be provided to enable

  Those skilled in the art can implement other embodiments based on the concepts just described without departing from the scope of the present invention.

  FIG. 6 illustrates such a further embodiment, where the membrane 700 has three series of through-holes 701 while the thin film 710 having a central hole 711 and a slit 712 has a single series of through-holes. Is provided so that it can be opened at any time. Here, the through-hole 701 is configured such that each series of through-holes corresponds to a predetermined fluid flow rate at a predetermined temperature. According to the illustrated embodiment, the first series of through holes corresponds to a fluid flow rate of 1 ml / h at 10 ° C., while the other two series of through holes are at 20 ° C. and 30 ° C., respectively. Corresponds to the same flow rate.

  Clearly, without departing from the scope of the present invention, a membrane with a further series of through-holes is provided such that the three series of through-holes correspond to a fluid flow rate of 2 ml / h at 10 ° C, 20 ° C and 30 ° C, respectively. Can be provided.

  The device may further be used for various fluid types having various viscosities. Therefore, a plurality of series of through holes can be configured in consideration of the use of such various fluids.

  A person skilled in the art will not encounter any difficulty to combine any of the embodiments, and the embodiment is a device that meets the needs of those skilled in the art, such as a series of through holes that consider both viscosity and temperature, for example. Has just been explained.

  The above description corresponds to preferred embodiments of the present invention described as non-limiting examples. In particular, there is no limit to the shape shown and described of the various component parts of the fluid flow regulator. For example, the number of through holes is not limited. Although the presence of the central through hole has been given as an illustrative example of an embodiment, those skilled in the art will not encounter the difficulty of constructing a fluid flow regulator without the central through hole.

  By way of example, those skilled in the art will not encounter any particular problems in applying the present invention to their needs with respect to dimensions, flow rates, materials, or fabrication method steps.

  It should also be noted that the device can be applied to the patient's skin or implanted into the patient's body, for example in the field of hydrocephalus treatment, which is typically guided by an implanted valve. Includes exhausted emissions.

  The following description is more specifically directed to the use of a regulator for draining cerebrospinal fluid (CSF) for hydrocephalus patients as an automatic regulating valve, and the description can be applied in principle to other applications. Is.

  FIG. 7 shows typical flow versus pressure characteristics for a passive self-adjusting hydrocephalus valve. The flow rate is adjusted to 20 ml / h at 10-35 mbar. This value corresponds to an average CSF production of 0.5 L / day. For daily high CSF production, it is necessary not to adjust at high pressure to prevent shortage of emissions. This explains the shape of the curve at high pressure. At low pressures, there is no longer a need for high flow rates (excess discharge problem). The flow rate can increase linearly from the threshold and varies from 3 to 10 mbar up to 20 ml / h.

  Excessive drainage due to patient movement causing hydrostatic pressure changes is strongly limited by this flow characteristic.

  This property is very close to one of the passive flow regulators described above. At high pressures, safety stop systems should be replaced with standard flow restrictors. This feature can be easily obtained by changing the position of the last hole of the device towards the outer edge of the membrane.

  The nominal characteristics of the device according to the invention are illustrated in FIG.

  The apparatus described above in this specification is based on the elastic deformation of the membrane that contacts the substrate when pressure is applied. The flow rate is adjusted through a small hole in the membrane.

  FEM simulations need to predict the initial shape of the membrane at various working pressures.

  Fluid simulation also needs to predict the behavior of the fluid at the exit of the hole. The small size of the gap between the membrane and the substrate connected to the large diameter of the membrane is very undesirable in terms of residual fluid resistance. The problem is that it is not axisymmetric and meshing with small holes and large fluid paths at these outlets is difficult.

  Solutions that partially avoid this effect are proposed in the disclosed embodiments. In addition, the flow rate prediction is significantly easier.

  The idea is simply to etch the substrate (RIE etc.) to create a pillar in front of the membrane hole. The aim is to ensure that the pressure tends to quickly exit pressure just behind the hole. It is also important to ensure that the membrane still undergoes symmetrical deformation. The outer ring of the substrate can be further etched for a better balance of pressure at the outlet. Various masks can be constructed on this etched portion.

  A very basic mask for etching the substrate is proposed below (see FIGS. 9, 10 and 11). The initial flat substrate 800 is first etched across a portion 801 that defines the diameter of the film (not shown here), typically by wet etching from silicon. Further etching (typically dry etching) is then performed to define the pillar 803 and the second height position of the chamber 804. The substrate (first etch height position 801) and the dark portion of the pillars 803 form a support for the membrane when pressure is applied. Reference numeral 805 is attached to the outlet of the valve.

  A schematic cross-sectional view of this system is illustrated in FIG. 11, which shows a post 803, an etching height location 804, and a membrane 3 having holes 15.

  The substrate can be formed from Pyrex, silicon or plastic. An anti-bonding layer for Pyrex or Si is required to prevent film sticking on the pillars during assembly.

  At a thickness of 100 μm, a 200 mm wafer can no longer support the wafer itself (150 μm for a 300 mm wafer). It is also necessary to use a substrate for handling problems, which can be removed after anodic bonding.

  In order to be sensitive to low pressure, it is necessary to use a thin film, or a small gap between the film and the substrate, or a large film diameter, or a combination thereof. A typical membrane shunt is very large, about 35 mm in diameter or more.

Maximum membrane diameter = 15 mm
Film thickness t fixed at t = 50 μm

  A contact pressure of 10 mbar results in a gap between the 25 μm film and the substrate.

  A flow can be modeled using a simple fluid resistance including holes and openings between the column and the membrane.

Hole fluid resistance Rf _i , hole diameter D _i , liquid dynamic viscosity η (in SI units):

A h _i (P) and _{D i} 'fluid resistance Rf _i of apertures _{comprising' (P), h i (} P) is located at a distance between the membrane and the bar at the pressure P about posts and holes l , D _i ′ is the diameter of the column, fluid resistance Rf _i ′ (P):

The flow rate Q takes the following form:

The function h _i (P) is predicted using the FEM model for membrane deformation due to pressure.

  The theoretical flow rate is consistent with using only three holes. Hole and column diameters are predicted using simulation. If the alignment tolerance between the hole and column is too tight, the number of holes can be varied. The holes placed in the outer part of the membrane do not have pillars.

  FIG. 12 illustrates a typical flow versus pressure simulation curve obtained for hydrocephalus.

  Another implementation with seven holes and pillars for drug delivery applications is as follows.

Silicon film diameter 5mm
50 μm thickness
25 μm gap

Features of 7 holes and columns:

  FIG. 13 illustrates the flow versus pressure simulation curves obtained with this implementation for drug delivery applications.

  As explained above, the system can regulate flow in both directions by placing another substrate on the front side of the membrane.

  Here, a substrate with pillars according to the principle described above can also be used for the bidirectional regulator. Since backflow is not allowed for the treatment of hydrocephalus (risk of contamination of ventricular germs), a simple check valve is required.

  In this case, the simplest way to create this check valve is to provide a similar substrate with a post 808 in front of the hole 15 (front side of the membrane 806) but without a gap (see FIG. 14). The new column 808 will change the fluid behavior of the system, and it is necessary to apply the previously described model for the simulation of fluid behavior.

  Typically, the film is pre-applied by adding a layer (preferably an anti-bonding layer) directly on the top substrate column 808 or directly on the film 806 to be pre-stressed. A slight tension can also be generated. This embodiment is schematically illustrated in FIG. 14, and the components described with respect to FIG. 11 have the same reference numbers in FIG. FIG. 14 clearly shows the new column 808 of the cover 807 in front of the column 803 (on the opposite side of the membrane 806).

  In a further embodiment of the invention, it is useful to know the intracranial pressure of the patient in order to check the efficiency of the treatment and the good functioning of the device. The pressure can be monitored by a physician using a wireless system.

  The pressure sensor itself can be easily made from a strain gauge embedded directly in the silicon film, and the silicon film receives a large stress due to the CSF pressure. This is a differential pressure sensor.

  Preliminary predictions of pressure sensor sensitivity are described below.

  Assumption: The electrical insulation of the bridge is made from a further embedded layer whose polarity is opposite to that of the resistor, in order not to introduce an additional physical layer (simplification of the method and good long-term stability) It will be.

Simulations have been performed to predict an appropriate amount of embedding.
Substrate: Silicon SC type n
Wafer (100)
Resistivity: 3-5 Ωcm
Geometrical arrangement of p-resistors along the [110] direction

A full bridge configuration is illustrated in FIG. Matched resistors R ₁ =. . . For = R ₄ = R, the following equation is obtained:

  An example of the geometry of resistors R1-R4 is illustrated in FIG.

となる。 With this geometry and system symmetry, the following equation is obtained:
ΔR ₁ = ΔR ₃ = −ΔR ₂ = −ΔR ₄ = ΔR
And finally:

It becomes.

The piezoresistive effect takes the following form.
ΔR / R = Π _l σ _l + Π _t σ _t
here,
_{Ｌ l} : longitudinal piezo resistivity Π _t : transverse piezo resistivity σ _l : stress along the resistor σ _t : stress along the direction perpendicular to the direction along the resistor (in-plane)

On a silicon (100) wafer, the piezoresistive effect is geometry dependent.
^{_{Π l = π 11 -sin 2 (}} 2θ) (π 11 -π 12 -π 44) / 2
_{Ｔ t} = π ₁₂ + sin ² (2θ) (π ₁₁ −π ₁₂ −π ₄₄ ) / 2
here,
Geometrical arrangement of resistors with respect to θ = [100] direction π ₁₁ , π ₁₂ and π ₄₄ : Piezoelectric resistivity n-Si: π ₁₁ = −102.2 (× 10 ⁻¹¹ Pa ⁻¹ )
π ₁₂ = 53.4 (× 10 ⁻¹¹ Pa ⁻¹ )
π ₄₄ = −13.6 (× 10 ⁻¹¹ Pa ⁻¹ )
p-Si: π ₁₁ = 6.6 (× 10 ⁻¹¹ Pa ⁻¹ )
π ₁₂ = −1.1 (× 10 ⁻¹¹ Pa ⁻¹ )
π ₄₄ = 138.1 (× 10 ⁻¹¹ Pa ⁻¹ )
(When ρ _n-Si = 11.7 Ωcm and ρ _p-Si = 7.8 Ωcm)

The following formula is obtained:

本願出願人の場合では、圧力は、膜の上表面（抵抗器側）に印加され、正圧のための正信号を得るために、Ｖ_ｏｕｔ＋及びＶ_ｏｕｔ−の極性を入れ替えるべきである。 By applying a positive pressure under the membrane, the signal becomes positive and can be expressed by the following equation.

In the Applicant's case, pressure should be applied to the top surface of the membrane (resistor side) and the polarity of V _{out +} and V _out− should be _reversed to obtain a positive signal for positive pressure.

  Stress is predicted for various pressures on the membrane. A non-linear model for film deflection is required because the deflection is large (the free deflection of the film without the substrate is greater than 0.4 times its thickness).

  FEM simulations show that non-linear effects can be neglected (membrane stress), and therefore the bending stress at the top membrane surface directly as a function of radial position at 40 mbar, as illustrated in FIG. Can be expected. Due to the large membrane diameter and thickness, the stress variation in the resistor can be ignored.

At 40 mbar, the following values are obtained near the edge of the membrane.

  This gradual change in stress with pressure at R = 7.35 mm is illustrated in FIG.

  The detector signal per volt bias is shown in FIG.

  It is also useful to show the sensitivity of the sensor per mbar pressure and per volt bias illustrated in FIG.

  At 20 mbar, the sensitivity S is about 0.5 mV / V / mbar.

  For a 2V bias, it is simply 1mV per mbar.

  The detector signal can be monitored without problems using a simple amplifier.

  A minimum resolution of 1 mbar is expected for this integrated pressure sensor.

  As illustrated in FIG. 21, it may be necessary to partially change the position of the interconnects outside the fluid path (resistors R1-R4 not to scale).

  Since there are no restrictions in the areas not covered by the n + layer, interconnects that do not come into contact with the liquid can be metallized or made by increasing the amount of p + layer.

  Electrical isolation of the interconnects and resistors can be obtained via a further non-conductive layer. This new layer should take into account the detector design (such as increased membrane stiffness).

  The regulator according to the invention will be readily understood from this description and from the non-exclusive examples, so that it can be used in various applications and in various ways and, if desired, for various applications. Embodiments can be combined with each other.

In addition, since the system according to the present invention may be sensitive to particles that may form a passage blockage, the device should therefore preferably include:
⇒ Filter located at the inlet.
⇒ Hydrophilic coating on rods and cylinders to prevent protein binding (eg PEG).

  Particle sensitivity should be considered during cleaning of various parts and assembly of equipment in a clean room.

  Many additional features can be implemented and the field of use can be extended to other applications other than drug delivery requiring the treatment of hydrocephalus or the same principle of function.

  Of course, other dimensions may be envisioned for other uses of the device, and all embodiments are shown as illustrative examples that should not be construed as limiting.

  As mentioned above, the description of the present invention has been made within the framework of drug delivery and hydrocephalus shunts for draining CSF, but is not limited to this special application, and in the medical field or Other applications in other fields may be envisaged. The possibility of integrating a pressure sensor inside the silicon film is a major advantage because the physician can monitor the CSF pressure from the outside using a wireless system. This device is passive and anti-siphonic due to its specific flow versus pressure characteristics. It is expected not to deteriorate. The apparatus can be tested using a gas flow meter at the height of the wafer. All materials that come into contact with the CSF are biocompatible materials.

  As will be appreciated from the previous description, the regulator can be used as a check valve (FIG. 14). The regulator can also be used as a valve that closes at high pressure, for example when the pressure reaches a predetermined high value (when the hole is closed because the membrane is completely deformed), or in a variant It can be ensured that the regulator is open even at high pressure, i.e. when the pressure reaches a predetermined high value. To this effect, it is necessary to place at least one hole near the side of the chamber 6 and therefore this hole is closed (as with the other holes) even when the membrane is completely deformed. Ensure that there is no. As will be appreciated, the characteristics of the regulator may be affected by the location of the holes and the number of holes.

  In the medical field, the device can be implanted or not implanted if necessary and can be made from a biocompatible material. Of course, other materials can be envisaged depending on the situation. Furthermore, other values are possible, and depending on the application, a given example is merely illustrative and not restrictive here.

  In addition, the size and shape of the regulators and devices can be varied as desired by those skilled in the art depending on the application and the desired effect.

  For example, the chambers on either side of the membrane (see FIGS. 4a, 4b and 14) can be identical or different from each other in size and shape.

  In addition, the pressure threshold (first, second, predetermined high value) can be selected and determined by the skilled worker depending on the application and / or use of the regulator.

  The material used can be of any type suitable for the intended use of the regulator. The material is a biocompatible material in the case of an implantable device. The material can be subjected to a special treatment and the material can be covered with a substance, for example a hydrophilic substance.

Claims (27)

A passive type fluid flow regulator (1) having a fluid inlet suitable for being connected to a fluid reservoir and a fluid outlet (13) suitable for being connected to a supply location,
The adjuster comprises a rigid substrate (2) and an elastic membrane (3), which are connected to a predetermined connecting part (4) so as to define a chamber (6) between the rigid substrate and the elastic membrane. Are firmly connected together,
The chamber (6) is connected to the fluid outlet (13) while the membrane (3) is on the opposite side of the chamber (6) connected to the fluid inlet the first surface (12). Have
The membrane (6) has a through hole (15) adjacent to the chamber to define a path for fluid from the fluid inlet to the fluid outlet (13), wherein the fluid is a first predetermined fluid. When a pressure larger than the threshold value is applied to the first surface (12), the substrate (2) can be brought into contact with the portion including the through hole (15) inside the chamber (6). To prevent fluid from flowing through the through-hole (15),
In the regulator,
The membrane (2) comprises at least one further through-hole (15) adjacent to the chamber (6);
When the further through-hole (15) applies a pressure to the first surface (12) where the fluid is greater than the first predetermined threshold but less than a second predetermined threshold, Configured to be able to flow through the further through hole,
The membrane (3) and the further through-hole (15) are further applied to the first surface (12) with a fluid flow rate approximately in the range from the first predetermined threshold to the second predetermined threshold. Configured to be approximately linear as a function of pressure being
The regulator. The membrane (3) comprises n further through-holes (15) adjacent to the chamber (6);
Each jth further through-hole applies the fluid to the first surface (12) with a pressure greater than the jth predetermined threshold but less than the (j + 1) th predetermined threshold. Is configured to flow through the j th further through hole,
The membrane and the n additional through-holes further provide a pressure applied to the first surface within a fluid flow rate range of approximately the first predetermined threshold to the (n + 1) th predetermined threshold. Configured to be approximately linear as a function,
The regulator (1) according to claim 1. Each of the through holes (15) has the first flow rate within a pressure range from approximately the first predetermined threshold to a corresponding predetermined upper threshold of each through hole so that the fluid flow rate is substantially constant. Configured to have a fluid resistance that increases linearly as a function of the pressure applied to the surface (12),
The regulator (1) according to claim 2. The through hole (15) has a shape without sharp edges;
The regulator (1) according to any one of claims 1 to 3. Each of the through holes (15) can have a shape such as a circle, an ellipse, an oblong and an elongated shape,
The regulator (1) according to claim 4. The through holes (15) are distributed across the membrane (3) along a helical curve;
The regulator (1) according to any one of claims 1 to 5. The through holes (15) are arranged in a series (602, 603, 604);
The regulator (1) comprises an occluding element (610, 710) disposed relative to the membrane (600, 700) such that the adjuster (1) is movable between at least a first position and a second position. And
The occlusive element is
Having at least one opening (612, 712);
At least one of the series of through-holes can be selectively blocked at the first position, and the series of through-holes are opened at the second position by matching the series of through-holes with the opening. Configured to be able to
The regulator of any one of Claims 2-6. The occlusive element is a thin film rotatable on the membrane;
The regulator according to claim 7. The occlusion element (610, 710) rotates between at least two different positions that adjust any one or any combination of parameters within a group including fluid flow rate, temperature, fluid viscosity or fluid properties. Configured to be possible,
The regulator according to claim 7 or 8. The conditioner comprises a further rigid substrate (420, 520);
A predetermined connecting portion on the first surface side such that the further rigid substrate defines a further chamber (406, 506) between the further rigid substrate (420, 520) and the elastic membrane (401, 501); Is firmly connected to the elastic membrane (401, 501),
Each additional rigid substrate has an inlet / outlet hole (421, 521) connected to a corresponding chamber;
The regulator of any one of Claims 1-6. Both the substrate and the film have a roughness in the range of 0.5-100 nm RMS at least at the binding portion (4);
The regulator of any one of Claims 1-10. Comprising at least one pillar (803) in front of the through hole (15) in the chamber (6);
The regulator of any one of Claims 1-11. Comprising at least one further column (808) on the opposite side of the through-hole (15);
The regulator according to claim 12. An additional column (808) opposite the through-hole (15) is in contact with the membrane to create a check valve;
The regulator according to claim 13. Comprising an anti-bonding layer on both or one of the membrane (3) and the pillars (803, 808),
The regulator of any one of Claims 1-14. Closing when the pressure reaches a predetermined high value,
The regulator according to any one of claims 1 to 15. Remains open even when the pressure reaches a predetermined high value,
The regulator according to any one of claims 1 to 15. Comprising means for measuring the deformation of the membrane;
The regulator of any one of Claims 1-17. Comprising a particle filter,
The regulator according to any one of claims 1 to 18. The part that comes into contact with the fluid is covered with a hydrophilic substance,
The regulator according to any one of claims 1 to 19. The deformation sensor is powered and monitored by external means,
The regulator according to any one of claims 1 to 20. A method for the production of a fluid flow regulator (1) according to any of the preceding claims,
a) providing an elastic membrane (3);
b) applying a sacrificial layer to the first surface (12) of the elastic membrane;
c) etching a plurality of holes in the membrane, wherein the sacrificial layer defines an etch stop;
d) applying a further layer to the sacrificial layer;
e) removing the sacrificial layer inside the hole;
f) The rigid substrate (2) at a predetermined coupling portion (4) opposite the first surface of the membrane so as to define a chamber (6) between the membrane and the rigid substrate (2). Assembling the membrane with the membrane,
g) removing the further layer in place so as to finish through-holes (15) in the membrane;
Including a stage consisting of:
Method. Step e) and step g) are performed simultaneously,
The method of claim 22. The further layer is a polymer layer applied by spraying, spinning or lamination,
24. A method according to claim 22 or 23. The substrate is etched to produce pillars and exit holes;
25. A method according to any one of claims 22 to 24. A drug injection device comprising a drug reservoir,
The drug reservoir
A fluid flow regulator (1) according to any of claims 1 to 21;
Infusion means for delivering a drug into the patient's body;
Connected to the
Drug infusion device.   An automatic adjustment valve for hydrocephalus comprising at least one regulator defined in one of claims 1 to 21.

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